N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof

ABSTRACT

N 2  -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No. 656,870 filed Feb. 10, 1976 which is a continuation-in-part of U.S. application Ser. No. 671,436 filed Mar. 29, 1976 and of U.S. application Ser. No. 671,568 filed Mar. 29, 1976 which are divisional applications of Ser. No. 622,390 filed Oct. 14, 1975, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the discovery of certain new and useful N² -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof, which are of especial value in view of their outstanding antithrombotic properties and low toxicities.

2. Description of the Prior Art

In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. The N² -(p-tolylsulfonyl)-L-arginine esters have been found to be one type of agent which can be used and these have been found to be effective in dissolving blood clots. (U.S. Pat. No. 3,622,615, issued Nov. 23, 1971).

One family of compounds which have been found to be particularly useful as highly specific inhibitors of thrombin for the control of thrombosis is the N² -dansyl-L-arginine ester or amide. (Our pending U.S. application Ser. No. 496,939, filed Aug. 13, 1974, now U.S. Pat. No. 3,978,045.) However, there is a continuing need for a highly specific inhibitor on thrombin for the control of thrombosis, which exhibits lower toxicity.

SUMMARY OF THE INVENTION

It has now been discovered that N² -arylsulfonyl-L-argininamides exhibit antithrombotic activity and even lower toxicity levels at the same relative potencies, as compared with the N² -dansyl-L-arginine ester or amide.

The compounds of this invention can be represented by the formula (I): ##STR1## wherein R₁ is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl and C₁ -C₁₀ alkoxy phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy and C₂ -C₂₀ dialkylamino, C₇ -C₁₂ aralkyl, ##STR2## wherein R₅ is hydrogen, C₁ -C₁₀ alkyl or C₁ -C₁₀ alkoxy; R₂ is selected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₂ -C₁₀ alkoxyalkyl, C₂ -C₁₀ alkylthioalkyl, C₂ -C₁₀ alkylsulfinylalkyl, C₁ -C₁₀ hydroxyalkyl, C₂ -C₁₀ carboxyalkyl, C₃ -C₁₀ alkoxycarbonylalkyl, C₁ -C₁₀ haloalkyl, C₇ -C₁₅ aralkyl, C₈ -C₁₅ α-carboxyaralkyl, C₃ -C₁₀ cycloalkyl and C₄ -C₁₀ cycloalkylalkyl; R₃ is selected from the group consisting of C₁ -C₅ alkyl, carboxy, C₂ -C₁₀ alkoxycarbonyl, phenyl, C₇ -C₁₂ aralkyl and ring substituted benzyl wherein said substituent is C₁ -C₅ alkyl or C₁ -C₅ alkoxy; R₄ is selected from the group consisting of C₁ -C.sub. 10 alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl and 5-indanyl; and n is an integer of 0, 1 or 2. Also encompassed within this invention are pharmaceutically acceptable salts thereof.

This invention also relates to a method for inhibiting activity and supressing activation of thrombin in vivo in mammals, which comprises administering to a mammal a pharmaceutically (antithrombotically) effective amount of N² -arylsulfonyl-L-argininamide or the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to a group of N² -arylsulfonyl-L-argininamides of the formula (I): ##STR3## wherein R₁ is selected from the group consisting of naphthyl, such as 1-naphthyl and 2-naphthyl, 5,6,7,8-tetrahydronaphthyl, such as 5,6,7,8-tetrahydro-1-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, such as fluoro, chloro, bromo and iodo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or the like and alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy or the like; phenyl, phenyl substituted with at least one substitutent selected from the group consisting of halo, such as fluoro, chloro, bromo and iodo, nitro, cyano, hydrosy, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy or the like, and dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, N-methyl-N-ethylamino or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, ##STR4## wherein R₅ is hydrogen, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl or the like, or alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy or the like; R₂ is selected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl of 3-10 (preferably 3-6) carbon atoms, such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl or the like, alkynyl of 3-10 (preferably 3-6) carbon atoms, such as 2-propynyl, 2-butynyl, 3-butynyl or the like, alkoxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl or the like, alkylthioalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl, 3-methylthiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl, 4-methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl or the like, alkylsulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl, 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl or the like, hydroxyalkyl of 1-10 (preferably 1-6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl or the like, carboxyalkyl of 2-10 (preferably 2-7) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 4-carboxybutyl or the like, alkoxycarbonylalkyl of 3-10 (preferably 3-8) carbon atoms, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, 4-methoxycarbonylbutyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl, 4-chlorobutyl or the like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 1-phenylethyl, 2-phenylpropyl or the like, α -carboxyaralkyl of 8-15 (preferably 8-12) carbon atoms, such as α -carboxybenzyl α -carboxyphenethyl or the like, C₃ -C₁₀ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl and C₄ -C₁₀ cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like; R₃ is selected from the group consisting of alkyl of 1-5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl or the like, carboxy, alkoxycarbonyl of 2-10 (preferably 2-5) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or the like, phenyl, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and ring substituted benzyl wherein said substituent is alkyl of 1-5 (preferably 1-3) carbon atoms, such as methyl, ethyl, propyl or isopropyl, or alkoxy of 1-5 (preferably 1-3) carbon atoms, such as methoxy, ethoxy, propoxy or isopropoxy; R₄ is selected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C₆ -C₁₀ aryl, such as phenyl, m-tolyl, p-tolyl, ethylphenyl, butylphenyl and naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; and n is an integer of 0, 1 or 2.

Suitable illustrations of R₁ in the above formula (I) are naphthyl, such as 1-naphthyl and 2-naphthyl, 5,6,7,8-tetrahydronaphthyl, such as 5,6,7,8-tetrahydro-1-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, such as chloro and bromo, hydroxy, C₁ -C₅ alkyl, such as methyl, ethyl and isopropyl, C₁ -C₅ alkoxy, such as methoxy and ethoxy, C₂ -C₁₀ dialkylamino, such as dimethylamino and diethylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, such as chloro, C₁ -C₅ alkyl, such as methyl, ethyl and isopropyl and C₁ -C₅ alkoxy, such as methoxy, C₇ -C₁₀ aralkyl, such as phenethyl, ##STR5## The preferred R₁ groups are 1-naphthyl, 2-naphthyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5-chloro-1-naphthyl, 6-chloro-2-naphthyl, 6-bromo-1-naphthyl, 5-hydroxy-1-naphthyl, 7-hydroxy-2-naphthyl, 6-methyl-2-naphthyl, 6-methyl-1-naphthyl, 7-methyl-1-naphthyl, 7-methyl-2-naphthyl, 6-ethyl-2-naphthyl, 6,7-dimethyl-1-naphthyl, 6,7-dimethyl-2-naphthyl, 6-isopropyl-2-naphthyl, 5-methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-naphthyl, 4,6-dimethoxy-2-naphthyl, 6,7-dimethoxy-2-naphthyl, 6,7-diethoxy-2-naphthyl, 5-dimethylamino-1-naphthyl, 5-dimethylamino-2-naphthyl, 5-diethylamino-1-naphthyl, 6-dimethylamino-1-naphthyl, 6-dimethylamino-2-naphthyl, 4-chlorophenyl, 2,4,5-trichlorophenyl, p-tolyl, anisyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, ##STR6## Suitable illustrations of R₂ in the above formula (I) are hydrogen, C₁ -C₁₀ alkyl, such as methyl, propyl, butyl, isobutyl, pentyl, hexyl and octyl, C₃ -C₆ alkenyl, such as allyl, C₃ -C₆ alkynyl, such as 2-propynyl, C₂ -C₆ alkoxyalkyl, such as 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyethyl and 3-methoxypropyl, C₂ -C₆ alkylthioalkyl, such as 2-ethylthioethyl and 2-methylthioethyl, C₂ -C₆ alkylsulfinylalkyl, such as 2-methylsulfinylethyl, C₁ -C₆ hydroxyalkyl, such as 2-hydroxyethyl and 3-hydroxybutyl, C₂ -C₇ carboxyalkyl, such as 1-carboxybutyl, C₃ -C₈ alkoxycarbonylalkyl, such as 2-ethoxycarbonylethyl, C₇ -C₁₀ aralkyl, such as benzyl and phenethyl, C₈ -C₁₂ α -carboxyaralkyl, such as α-carboxyphenethyl, C₃ -C₁₀ cycloalkyl, such as cyclopropyl, cyclohexyl and cycloheptyl, and C₄ -C₁₀ cycloalkylalkyl, such as cyclohexylmethyl.

Suitable illustrations of R₃ in the above formula (I) are C₁ -C₅ alkyl, such as methyl and propyl, carboxy, C₂ -C₅ alkoxycarbonyl, such as ethoxycarbonyl, C₇ -C₁₀ aralkyl, such as benzyl, and ring substituted benzyl wherein said substituent is C₁ -C₃ alkoxy, such as 4-methoxybenzyl.

Suitable R₄ groups in the above formula (I) are hydrogen, C₁ -C₁₀ alkyl, such as methyl, ethyl, tert-butyl and octyl, C₆ -C₁₀ aryl, such as phenyl and m-tolyl, C₇ -C₁₀ aralkyl, such as benzyl, and 5-indanyl.

Illustrative of suitable N² -arylsulfonyl-L-argininamides of sufficient activity of this invention are the following:

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylalanine tert-butyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-pentylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-pentylalanine tert-butyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine tert-butyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylalanine tert-butyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylalanine tert-butyl ester

N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylmethylalanine

N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylmethylalanine tert-butyl ester

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-propylalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-propylalanine tert-butyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)alanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylaspartic acid

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylaspartic acid α, β-diethyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-methylphenylalanine

N² -(7-methoxy2-naphthylsulfonyl)-L-arginyl-N-methyl-β-(p-methoxyphenyl)alanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-methyl-phenylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginylnorvaline

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylaspartic acid

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylaspartic acid α, β-diethyl ester

Of the compounds of this invention, it will be understood that the following compounds are most preferred due to their high level of antithrombotic activity and low level of toxicity.

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)alanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginylnorvaline

The pharmaceutically acceptable salts of the above compounds are of course also included within the scope of this invention. The above compounds are intended only to illustrate the variety of structures which can be used in the process of this invention, and the above listing is not be construed as limiting the scope of the invention. For the preparation of the compounds of this invention, various methods can be employed depending upon the particular starting materials and/or intermediates involved. Successful preparation of these compounds is possible by way of several synthetic routs which are outlined below.

(a) Condensation of an L-argininamide with an arylsulfonyl halide

This process may be illustrated as follows: ##STR7## In the above formulas, R₁, R₂, R₃, R₄ and n are as defined herein above, and X is halogen. The N² -arylsulfonyl-L-argininamide (I) is prepared by the condensation of aN L-argininamide (II) with a substantially equimolar amount of an arylsulfonyl halide (III), preferably a chloride.

The condensation reaction is generally effected in a suitable reaction-inert solvent in the presence of an excess of a base, such as an organic base (triethylamine, pyridine) or a solution of an inorganic base (sodium hydroxide, potassium carbonate), at a temperature of 0° C to the boiling temperature of the solvent for a period of 10 minutes to 15 hours. The preferred solvents for the condensation include benzene-diethyl ether, diethyl ether-water and dioxane-water.

After the reaction is complete, the formed salt is extracted with water, and the solvent is removed by such standard means as evaporation under reduced pressure to give the N² -arylsulfonyl-L-argininamide (I), which can be purified by trituration or recrystallization from a suitable solvent, such as diethyl ether-tetrahydrofuran, diethyl ether-methanol and water-methanol, or may be chromatographed on silica gel. The L-argininamides (II) starting materials required for the condensation reaction can be prepared by protecting the guanidino and α-amino groups of the L-arginine via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation or tritylation and then condensing the formed N^(G) -substituted -N² -substituted-L-arginine with a corresponding amino acid derivative by such a conventional process as the acid chloride method, azide method, mixed anhydride method, activated ester method or carbodiimide method, and thereafter selectively removing the protective groups.

(b) Removal of the N^(G) -substituent from an N^(G) -substituted-N² -arylsulfonyl-L-argininamide

This process may be illustrated as follows: ##STR8##

In the above formulas, R₁, R₂, R₃, R₄, n and X are as defined herein above; Y" is a protective group for the amino group, such as benzyloxycarbonyl or tert-butoxycarbonyl; and Y and Y' are hydrogen and protective groups for the guanidino group, such as nitro, tosyl, trityl, oxycarbonyl or the like. At least one of Y and Y' is a protective group for the guanidino group.

The N² -arylsulfonyl-L-argininamide (I) is prepared by removing the N^(G) -substituent from an N^(G) -substituted-N² -arylsulfonyl-L-argininamide (III) by means of acidolysis or hydrogenolysis.

The acidolysis is generally effected by contacting the N^(G) -substituted-N² -arylsulfonyl-L-argininamide (III) and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or in a solvent, such as an ether (tetrahydrofuran, dioxane), an alcohol (methanol, ethanol) or acetic acid at a temperature of -10° C to 100° C, and preferably at room temperature for a period of 30 minutes to 24 hours.

The products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable solvent followed by filtration and drying.

Because of the use of the excess acid, the products are generally the acid addition salts of the N² -arylsulfonyl-L-argininamides (I), which can be easily converted to a free amide by neutralization.

The removal of the nitro group and the oxycarbonyl group, e.g., benzyloxycarbonyl, p-nitrobenzyloxy-carbonyl, is readily accomplished by the hydrogenolysis. The hydrogenolysis is effected in a reaction-inert solvent, e.g., methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activating catalyst, e.g., Raney nickel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0° C to the boiling temperature of the solvent for a period of 2 hours to 120 hours.

The hydrogen pressure is not critical, and atmosphere pressure is sufficient.

The N² -arylsulfonyl-L-argininamides (I) are isolated by filtration of the catalyst followed by evaporation of the solvent.

The N² -arylsulfonyl-L-argininamides can be purified in the same manner as described above. The N^(G) -substituted-N² -arylsulfonyl-L-argininamides (VIII) starting materials can be prepared by condensing an N^(G) -substituted-N² -substituted L-arginine (IV) (generally the N² -substituent is a protective group for the amino group, such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a corresponding amino acid derivative (V) via the azide method, mixed anhydride method, activated ester method, carbodiimido method or the like, selectively removing only the N² -substituent of an N^(G) -substituted-N² -substituted L-argininamide (VI) by means of catalytic hydrogenolysis or acidolysis, and then condensing the thus obtained N^(G) -substituted-L-argininamide (VII) with an arylsulfonyl halide (III), preferably a chloride in the presence of a base in a solvent. These reaction conditions are as described above in the condensation of an L-argininamide with an arylsulfonyl halide, and the removal of the N^(G) -substituent from an N^(G) -substituted-N² -arylsulfonyl-L-argininamide.

(c) Condensation of an N² -arylsulfonyl-L-arginyl halide with an amino acid derivative

This process may be illustrated as follows: ##STR9## In the above formulas, R₁, R₂, R₃, R₄, n and X are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by the condensation of an N² -arylsulfonyl-L-arginyl halide (IX), preferably a chloride with at least an equimolar amount of an amino acid derivative (V).

The condensation reaction can be carried out without an added solvent. However, satisfactory results will be obtained with the use of a solvent such as basic solvents (dimethylformamide, dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.).

The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of the N² -arylsulfonyl-L-arginyl halide (IX).

Preferred condensation reaction temperatures are in the range of from -10° C to room temperature. The reaction time is not critical, but varies with the amino acid derivative (V) employed. In general, a period of from 5 minutes to 10 hours is operable.

The obtained N² -arylsulfonyl-L-argininamide can be isolated and purified in the same manner as described above.

The N² -arylsulfonyl-L-arginyl halide (IX) starting materials required for the condensation reaction can be prepared by reacting an N² -arylsulfonyl-L-arginine with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or phosphorus tribromide. The halogenation can be carried out with or without an added solvent.

The preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxane.

The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of the N² -arylsulfonyl-L-arginine. Preferred reaction temperatures are in the range of -10° C to room temperature. The reaction time is not critical, but varies with the halogenating agent and reaction temperature. In general, a period of 15 minutes to 5 hours is operable.

(d) Guanidylation of an N² -arylsulfonyl-L-ornithinamide or an acid addition salt thereof

This process may be illustrated as follows: ##STR10## In the above formulas, R₁, R₂, R₃, R₄ and n are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by guanidylating an N² -arylsulfonyl-L-ornithinamide (X) with an ordinary guanidylating agents such as an O-alkylisourea, S-alkylisothiourea, 1-guanyl-3,5-dimethylpyrazole or carbodiimide. The preferred guanidylating agents are the O-alkylisourea and the S-alkylisothiourea.

The guanidylation of the N² --arylsulfonyl-L-ornithinamide (X) with the O-alkylisourea or S-alkylisothiourea is generally effected in a solvent in the presence of a base at a temperature of from 0° C to the boiling temperature of the solvent for a period of from 30 minutes to 50 hours.

Examples of the preferred base are triethylamine, pyridine, sodium hydroxide and sodium methoxide. The base is used in an amount of 0.01 to 0.1 equivalent to the N² -arylsulfonyl-L-ornithinamide. Examples of the preferred solvent are water, water-ethanol and water-dioxane.

After the reaction is complete, the N² -arylsulfonyl-L-argininamide (I) is isolated by evaporation of the solvent followed by removal of the excess base and the formed salt by a water wash.

It is well recognized in the art that an ester derivative of the N² -arylsulfonyl-L-argininamide (I) wherein R₄ is alkyl, aryl, aralkyl or 5-indanyl, can be prepared from a carboxylic acid derivative of the N² -arylsulfonyl-L-argininamide wherein R₄ is hydrogen, by the conventional esterification methods well known to those skilled in the art. It is also well recognized in the art that the carboxylic acid derivative can be prepared from the ester derivative by the conventional hydrolysis or acidolysis methods. The conditions under which esterification, hydrolysis or acidolysis would be carried out will be each apparent to those skilled in the art.

The N² -arylsulfonyl-L-argininamide (I) of this invention forms acid addition salts with any of a variety of inorganic and organic acids. Some of the N² -arylsulfonyl-L-argininamide containing a free carboxy group, wherein R₄ is hydrogen, forms salts with any of a variety of inorganic and organic bases. The product of the reactions described above can be isolated in the free form or in the form of salts.

In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like. In a similar manner, the product can be obtained as pharmaceutically acceptable salts by reacting one of the free carboxylic acids with a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.

Likewise, treatment of the salts with a base or acid results in a regeneration of the free amide.

As stated above, the N² -arylsulfonyl-L-argininamides, and the salts thereof of this invention are characterized by highly specific inhibitory activity against thrombin in mammals as well as by their substantial lack of toxicity, and therefore these compounds are useful in the determination of thrombin in blood as diagnostic reagents, and/or for the medical control or prevention of thrombosis.

The antithrombotic activities of the N² -arylsulfonyl-L-argininamide of this invention were compared with that of a known antithrombotic agent, N² -(p-tolysulfonyl)-L-arginine methyl ester, by determining the fibrinogen coagulation time. The measurement of the fibrinogen coagulation time was conducted as follows:

An 0.8 ml aliquot of a fibrinogen solution, which had been prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied by Armour Inc. in 40 ml of a borate saline buffer (pH 7.4), was mixed with 0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solution in the same buffer, and 0.1 ml of a thrombin solution (5 units/ml) supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutions in an ice bath. Immediately after mixing, the reaction mixture was transferred from the ice bath to a bath maintained at 25° C. Coagulation times were taken as the period between the time of transference to the 25° C bath and the time of the first appearance of fibrin threads. In the cases where no drug samples were added, the coagulation time was 50-55 seconds.

The experimental results are summarized in Table 1. The term "concentration required to prolong the coagulation time by a factor of two" is the concentration of an active ingredient required to prolong the normal coagulation time 50-55 seconds to 100-110 seconds.

The concentration required to prolong the coagulation time by a factor of two for the known antithrombotic agent, N² -(p-tolylsulfonyl)-L-arginine methyl ester, was 1,100μM. The inhibitors are shown in Table 1 by indicating R₁, R₂, R₃, R₄ and n in the formula (I) and the addition moiety. When a solution containing an N² -arylsulfonyl-L-argininamide of this invention was administered intravenously into animal bodies, the high antithrombotic activity in the circulating blood was maintained for from one to three hours. The halflife for decay of the antithrombotic compounds of this invention in circulating blood was shown to be approximately 60 minutes; the physiological conditions of the host animals (mammals such as rat, rabbit, dog and chimpanzee) were well maintained. The experimental decrease of fibrinogen in animals caused by infusion of thrombin was satisfactorily controlled by simultaneous infusion of the compounds of this invention.

The acute toxicity values (LD₅₀) determined by intraperitoneal administration of substances of formula (I) in mice (male, 20 g) range from about 1,000 to 10,000 milligrams per kilogram of body weight. Representative LD₅₀ values, for example, for N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylalanine and N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylmethylalanine are above 1,500 milligrams per kilogram each.

On the other hand, LD₅₀ values for N² -dansyl-N-butyl-L-argininamide and N² -dansyl-N-methyl-N-butyl-L-argininamide are 75 and 70 milligrams per kilogram, respectively. The therapeutic agents of this invention may be administered to mammals, including humans alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, the compounds may be injected parenterally, that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The compounds may be administered orally in the form of solutions which may contain coloring and flavoring agents.

Physicians will determine the dosage of the present therapeutic agents which will be most suitable for humans, and dosages vary with the mode of administration and the particular compound chosen. In addition, the dosage will vary with the particular patient under treatment.

When the composition is administered orally, a larger quantity of the active agent will be required to produce the same effect as caused with a smaller quantity given parenterally. The therapeutic dosage is generally 10-50 mg/kg of active ingredient parenterally, 10-500 mg/kg orally per day.

Having generally described the invention, a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise specified.

EXAMPLE 1

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylalanine

To a solution of 3.00 g of N^(G) -nitro-N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylalanine benzyl ester in 50 ml of acetic acid was added 0.5 of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion .sup.® SK 102 ion exchange resin (200-300 mesh, H⁺ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide was evaporated to dryness to give 1.64 g (67%) of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylalanine as an amorphous solid.

I.R. (KBr): 3,360, 3,160, 1,600 cm⁻¹ Analysis - Calcd. for C₂₉ H₃₇ N₅ O₇ S (percent): C, 58.08; H, 6.22; N, 11.68 Found (percent): C, 57.84; H, 6.13; N, 11.46

EXAMPLE 2

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine

(A) N-benzylalanine tert-butyl ester To 65.0 g of benzylamine in 100 ml of benzene was added with stirring 25.0 g of tert-butyl 2-chloroproprionate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C for an additional one hour. At the end of this period, the reaction mixture was taken up in 70 ml of 2N NaOH solution and 80 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered.

After evaporation of benzene, the residue was distilled under reduced pressure to give 33.2 g (90.0 percent) of N-benzylalanine tert-butyl ester, B.P. 164° C/14 mmHg.

Analysis - Calcd. for C₁₄ H₂₁ NO₂ (percent): C, 71.45; H, 7.00; N, 5.95 Found (percent): C, 71.38; H, 6.98; N, 5.96

(b) n² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride A suspension of 2.00 g of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride.

(C) N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine tert-butyl ester

To a stirred solution of 4.42 g of N-benzylalanine tert-butyl ester in 20 ml of chloroform was carefully added N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was allowed to stand at room temperature for one hour. At the end of this period, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness to give 2.50 g (83 percent) of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine tert-butyl ester in the form of a powder. The flavianate; M.P. 168°-172° C (dec.)

I.R. (KBr): 3,380, 3,180, 1,740 cm⁻¹ Analysis - Calcd. for C₃₂ H₄₃ O₇ N₅ S.C₁₀ H₆ O₈ N₂ S (percent): C, 52.77; H, 5.17; N, 10.26 Found (percent): C, 52.54; H, 4.98; N, 10.21

(d) n² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine

To a solution of 2.00 g of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine tert-butyl ester in 20 ml of chloroform was added 30 ml of trifluoroacetic acid.

The reaction mixture was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion ® SK 102 ion exchange resin (200-300 mesh, H⁺ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.26 g (69 percent) of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine as an amorphous solid.

I.R. (KBr): 3,350-3,160 (broad), 1,600 cm⁻¹ Analysis - Calcd. for C₂₈ H₃₅ N₅ O₇ S (percent): C, 57.42; H, 6.02; N, 11.96 Found (percent): C, 57.35; H, 5.84; N, 12.00

EXAMPLE 3

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-methylphenylalanine:

A solution of 2.5 g of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-methylphenylalanine ethyl ester in 5 ml of ethanol and 7 ml of 1N NaOH solution was stirred for 30 hours at room temperature. At the end of this period, the solution was concentrated to 5 ml, chromatographed on 80 ml of Daiaion ® SK 102 ion exchange resin (200-300 mesh, H⁺ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness, and the residue was purified by reprecipitation with ethanol-diethyl ether to give 1.86 g (78 percent) of N² -(6,7-dimethoxy-2-naphthyl-sulfonyl)-L-arginyl-N-methylphenylalanine as an amorphous solid, I.R. (KBr): 3,300 (broad), 1,600 cm⁻¹

Analysis - Calcd. for C₂₈ H₃₅ N₅ O₇ S (percent): C, 57.42; H, 6.02; N, 11.96 Found (percent): C, 57.37; H, 5.86; N, 11.74

Various other N² -alkoxynaphthylsulfonyl-L-argininamides or acid addition salts thereof were synthesized in accordance with the procedure of the above examples, and the test results are summarized in Table 1.

    TABLE I              Sam-ple       ##STR11##       Concentrationrequired toprolong thecoagulationtime by afactor of two      Prepara-tionprocess m.p. Elementary analysisUpper: Calculated(%)Lower:      Found (%) I.R. (KBr) No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 nAddition      moiety (μM) (Ex. No.) (°       C) C H N (cm.sup.-1)                                  1       ##STR12##      (CH.sub.2).sub.3       CH.sub.3 CH.sub.3 C(CH.sub.3).sub.3 0      ##STR13##       2 165-170(dec.) 50.8150.68 5.585.43 10.6410.31 3,3803,2001,740 2       ##STR14##       (CH.sub.2).sub.3 CH.sub.3 " H " --  2 powder 54.4354.70 6.766.71      12.7012.35 3,4001,590 3       ##STR15##       (CH.sub.2).sub.4       CH.sub.3 " C(CH.sub.3).sub.3 "      ##STR16##        2 164-166  51.3351.605.715.38 10.4810.25 3,3603,2001,735 4       ##STR17##       (CH.sub.2).sub.4 CH.sub.3 " H " -- 2.0 2 powder 55.2155.00 6.956.30      12.3812.40 3,400-3,200(broad)1,570 5       ##STR18##       ##STR19##       " C(CH.sub.3).sub.3 "       ##STR20##        2 168-172 52.7752.54 5.174.98 10.2610.21 3,3803,1801,740 6       ##STR21##       ##STR22##       " H " -- 2.5 2 powder 57.4257.35 6.025.84 11.9612.00 3,350-3,160(broad)1      ,600 7       ##STR23##       ##STR24##       " C(CH.sub.3).sub.3 "       ##STR25##       2 130-135 53.2553.08 5.305.29 10.1110.29 3,4003,2001,730 8       ##STR26##       ##STR27##       CH.sub.3 H "  1.5 1 powder 58.0857.84 6.226.13 11.6811.46 3,3603,1601,60      0 9       ##STR28##       ##STR29##       "C(CH.sub.3).sub.3 "       ##STR30##        2 158-163(dec) 51.9551.80 5.645.38 10.3410.30 3,3603,2001,740 10       ##STR31##       ##STR32##       " H "   2 powder 56.1455.98 6.816.79 12.1312.35 3,380-3,200(broad)1,625      11       ##STR33##       ##STR34##       " C(CH.sub.3).sub.3 "       ##STR35##        2 160-163(dec) 52.4452.39 5.765.58 10.1910.00 3,4003,2001,740 12       ##STR36##       ##STR37##       " H "  4.5 2 powder 56.8456.72 6.996.80 11.8411.76 3,380-3,250(broad)1,5      95 13       ##STR38##       (CH.sub.2).sub.2       CH.sub.3 " C(CH.sub.3).sub.3 "      ##STR39##        2 160-165(dec) 50.6250.39 5.40 5.28 11.1711.15 3,4003,2101,740 14       ##STR40##       (CH.sub.2).sub.2       CH.sub.3 " H "   1 powder 54.4354.27 6.556.28 13.8013.59 3,2801,590 15       ##STR41##       CH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 H " --  5 2 powder 52.0751.89      6.376.39 12.6512.51 3,3603,2001,600 16       ##STR42##       ##STR43##       COONH.sub.4 H 1 --  2, 3 powder 53.8654.16 5.925.62 13.0012.70 3,100      (broad)1,620 17       ##STR44##       " COOC.sub.2 H.sub.5 C.sub.2 H.sub.5 1 1/2 H.sub.2 SO.sub.3  2. 3      powder 54.5354.23 6.105.80  9.64       9.34 1,7201,630 (broad) 18      ##STR45##       CH.sub.3       ##STR46##       H 0 -- 2 2, 3 powder 57.4257.37 6.025.86 11.9611.74 3,300 (broad)1,600      19       ##STR47##       CH.sub.3       ##STR48##       H 0--  2, 3 powder 57.4157.33 6.035.94 11.9611.73 3,3001,610 20       ##STR49##       CH.sub.3       ##STR50##       Na 0 -- 2.5 2, 3 powder 53.9853.74 5.385.33 11.6611.74 3,3501,630 21       ##STR51##       H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H 0 -- 15 2, 3 powder 52.7552.68      6.366.34 13.3813.41 3,380 (broad)1,620 22       ##STR52##       CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 COONH.sub.4 H 1 -- 2, 3 powder      5      50.970.67 6.586.61 13.72 13.39 3,200 (broad)1,610 (broad) 23       ##STR53##       " COOC.sub.2 H.sub.5 C.sub.2 H.sub.5 1 1/2 H.sub.2 SO.sub.3  2, 3      powder 52.01 51.77 6.696.50 10.1110.00 1,7251,620

The following compounds are prepared in a similar manner:

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-ethyl)alanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)alanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butylalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-pentylalanine

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-isobutyl-alanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-phenyl-propyl)alanine

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-benzylalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexyl-alanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexyl-methylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylbutyrine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)norvaline

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylleucine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylnorleucine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butylisoleucine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-pentylbutyrine

N² -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cycloheptylalanine

EXAMPLE 4

Tablets suitable for oral administration. Tablets containing the ingredients indicated below may be prepared by conventional techniques.

    ______________________________________                                                                  Amount per                                                       Ingredient    tablet (mg)                                           ______________________________________                                         N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-                                                            250                                                   L-arginyl-N-(2-methoxyethyl)alanine                                            Lactose                  140                                                   Corn starch              35                                                    Talcum                   20                                                    Magnesium stearate       5                                                     Total                    450 mg                                                ______________________________________                                    

EXAMPLE 5

Capsules for oral administration.

Capsules of the below were made up by thoroughly mixing together batches of the ingredients and filling hard gelatin capsules with the mixture.

    ______________________________________                                                                  Amount per                                                                     capsule                                               Ingredient               (mg)                                                  ______________________________________                                         N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-                                                            250                                                   L-arginyl-N-(2-methoxyethyl)alanine                                            Lactose                  250                                                   Total                    500 mg                                                ______________________________________                                    

EXAMPLE 6

Sterile solution for infusion

The following ingredients are dissolved in water for intravenous perfusion and the resulting solution is then sterilized.

    ______________________________________                                                                   Amount                                               Ingredients               (g)                                                  ______________________________________                                         N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-                                                             25                                                   L-arginyl-N-(2-methoxyethyl)alanine                                            Buffer system             As desired                                           Glucose                   25                                                   Distilled water           500                                                  ______________________________________                                    

PREPARATION A Amino Acid tert-Butyl Esters

The following amino acid tert-butyl esters not previously reported in the chemical literature were synthesized by the aforementioned procedure of Example 2 (A) which is essentially that as taught by A. J. Speziale et al., J. Org. Chem., 25 731 (1960).

    ______________________________________                                         No.   Amino Acid Derivative                                                                              B.P.                                                 ______________________________________                                                ##STR54##          93° C/26 mmHg                                 2                                                                                     ##STR55##          110° C/27 mmHg                                3                                                                                     ##STR56##          124° C/26 mmHg                                4                                                                                     ##STR57##          88-90° C/6 mmHg                               5                                                                                     ##STR58##          116-8° C/2 mmHg                               6                                                                                     ##STR59##          167° C/16 mmHg                                7                                                                                     ##STR60##          125° C/16 mmHg                                8                                                                                     ##STR61##          141° C/15 mmHg                                ______________________________________                                    

Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit of the invention as set forth herein. 

What is claimed as new and intended to be covered by letters patent is:
 1. N² -arylsulfonyl-L-argininamides having the formula (I): ##STR62## and the pharmaceutically acceptable salts thereof, wherein R₁ is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl subsituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl and C₁ -C₁₀ alkoxy, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy and C₂ -C₂₀ dialkylamino, C₇ -C₁₂ aralkyl, ##STR63## wherein R₅ is hydrogen, C₁ -C₁₀ alkyl or C₁ -C₁₀ alkoxy; R₂ is selected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₂ -C₁₀ alkoxyalkyl, C₂ -C₁₀ alkylthioalkyl, C₂ -C₁₀ alkylsulfinylalkyl, C₁ -C₁₀ hydroxyalkyl, C₂ -C₁₀ carboxyalkyl, C₃ -C₁₀ alkoxycarbonylalkyl, C₁ -C₁₀ haloalkyl, C₇ -C₁₅ aralkyl, C₈ -C₁₅ α -carboxyaralkyl, C₃ -C₁₀ cycloalkyl and C₄ -C₁₀ cycloalkylalkyl; R₃ is selected from the group consisting of C₁ -C₅ alkyl, carboxy, C₂ -C₁₀ alkoxycarbonyl, phenyl, C₇ -C₁₂ aralkyl and ring substituted benzyl wherein said substituent is C₁ -C₅ alkyl or C₁ -C₅ alkoxy; R₄ is selected from the group consisting of C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl and 5-indanyl; and n is an integer or 0, 1 or
 2. 2. The compound of claim 1, wherein R₁ is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₅ alkyl and C₁ -C₅ alkoxy, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₅ alkyl, C₁ -C₅ alkoxy and C₂ -C₁₀ dialkylamino, C₇ -C₁₀ aralkyl, ##STR64## wherein R₅ is hydrogen, C₁ -C₅ alkyl or C₁ -C₅ alkoxy; R₂ is selected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, C₃ -C₆ alkenyl, C₃ -C₆ alkynyl, C₂ -C₆ alkoxyalkyl, C₂ -C₆ alkylthioalkyl, C₂ -C₆ alkylsulfinylalkyl, C₁ -C₆ hydroxyalkyl, C₂ -C₇ carboxyalkyl, C₃ -C₈ alkoxycarbonylalkyl, C₇ -C₁₀ aralkyl, C₈ -C₁₂ α -carboxyaralkyl, C₃ -C₁₀ cycloalkyl and C₄ -C₁₀ cycloalkylalkyl; R₃ is selected from the group consisting of C₁ -C₅ alkyl, carboxy, C₂ -C₅ alkoxycarbonyl, C₇ -C₁₀ aralkyl and ring substituted benzyl wherein said substituent is C₁ -C₃ alkoxy; R₄ is selected from the group consisting of C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -C₁₀ aralkyl and 5-inddanyl; and n is an integer of 0, 1, or
 2. 3. The compound of claim 2, wherein R₁ is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, hydroxy, C₁ -C₅ alkyl and C₁ -C₅ alkoxy, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, C₁ -C₅ alkyl and C₁ -C₅ alkoxy, C₇ -C₁₀ aralkyl, ##STR65##
 4. A compound of claim 3, which is N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)alanine.
 5. A compound of claim 3, which is N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylalanine.
 6. A compound of claim 3, which is N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine.
 7. A compound of claim 3, which is N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylalanine.
 8. A compound of claim 3, which is N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginylnorvaline.
 9. A method of inhibiting activity and suppressing activation of thrombin in vivo, which comprises administering to a mammal a pharmaceutically effective amount of an N² -arylsulfonyl-L-argininamide having the formula (I): ##STR66## or the pharmaceutically acceptable salt thereof wherein R₁ is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl and C₁ -C₁₀ alkoxy, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy and C₂ -C₂₀ dialkylamino, C₇ -C₁₂ aralkyl, ##STR67## wherein R₅ is hydrogen, C₁ -C₁₀ alkyl or C₁ -C₁₀ alkoxy: R₂ is selected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₂ -C₁₀ alkoxyalkyl, C₂ -C₁₀ alkylthioalkyl, C₂ -C₁₀ alkylsulfinylalkyl, C₁ -C₁₀ hydroxyalkyl, C₂ -C₁₀ carboxyalkyl, C₃ -C₁₀ alkoxycarbonylalkyl, C₁ -C₁₀ haloalkyl, C₇ -C₁₅ aralkyl, C₈ -C₁₅ α -carboxyaralkyl, C₃ -C₁₀ cycloalkyl and C₄ -C₁₀ cycloalkylalkyl; R₃ is selected from the group consisting of C₁ -C₅ alkyl, carboxy, C₂ -C₁₀ alkoxycarbonyl, phenyl, C₇ -C₁₂ aralkyl and ring substituted benzyl wherein said substituent is C₁ -C₅ alkyl or C₁ -C₅ alkoxy; R₄ is selected from the group consisting of C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl and 5-indanyl; and n is an integer of 0, 1 or
 2. 